PROJECT SUMMARY Our longitudinal design of alcohol self-administration in the non-human primate has yielded evidence of stress axis risk factors associated in the development of heavy alcohol drinking as well as an impairment in brain regions involved in the control of voluntary actions. In this proposal, we will examine the ability of manipulating stress circuitry by inhibiting glucocorticoid receptors to decrease heavy ethanol drinking and relapse. We will also test the hypothesis that heavy alcohol drinking leads to impairments of the neural control of voluntary actions that involves a relative shift in activation of cortico-basal ganglia circuitry between the associative and sensorimotor subcircuits in response to context, contingencies and the predicted outcome of the action. The associative circuitry, involving prefrontal cortical projections to the caudate nucleus, is implicated in flexible adjustments to behavior. The sensorimotor circuitry, on the other hand, involves sensorimotor and motor cortical projections to the putamen and controls habitual behaviors. We will use baseline resting-state functional connectivity with MRI to investigate if individual differences in cortico-basal ganglia connectivity are associated with performance on a self-paced set shifting task as well as heavy alcohol consumption. Designer receptors exclusively activated by designer drug (DREADDs) will be implemented to alter cortico-basal ganglia circuits and examine effects on cognitive flexibility and heavy ethanol drinking. Resting-state fMRI will then be used to verify the changes in connectivity strength by the activation of DREADDs, so that this less invasive method can be positioned to identify abnormal functioning of cortico-basal ganglia subcircuits. This highly innovative research in macaque monkeys will advance the application of neurotechnologies to understand and modulate addiction, a maladaptive behavior.